Epidermal growth factor (EGF) receptor is a cell surface receptor involved in a number of cancers. Inhibition of its intracellular kinase domain with small molecules has recently been proven to have clinical efficacy. We propose a novel approach to block activation of the EGF receptor using small molecules that bind to the extracellular domain, thus attenuating the signaling of EGF at an earlier intervention point - one that, importantly, does not require cell penetration by drug. Small molecules will be designed to mimic the critical exposed receptor-binding residues on the EGF molelcular surface, so that they are able to bind to the receptor in competition with the natural ligand EGF. In order to explore the "bioactive" conformations of EGF, an ensemble of structures of EGF will be generated using molecular dynamics simulation along with structures determined using NMR. Dynamic pharmacophores will be derived from the ensemble and used in a virtual screen of a small molecule database. Phase I of this project includes the following objectives: 1) generation of a 3-D dynamic model of EGF, 2) identification of surface aminoacyl side chains which participate in ligand-receptor binding to generate pharmacophore templates, 3) identification of non-peptide chemicals that match the template, and 4) evaluation of biochemical and pharmacological activities of the selected compounds. The goal of Phase I is to identify antagonist activity in the range of 1-20 micromolar. The success of Phase I will lead to Phase II refinement of the initial leads into pre-clinical candidates for EGF receptor antagonism. PROPOSED COMMERCIAL APPLICATION: Cancer is a major cause of death threatening human lives at all ages. Aberrant expression of the EGF receptor has been observed in many cancers including those of the brain, head and neck, breast, lung and bladder, and is a major cause of the malignant processes. Antagonists acting through a novel extracellular interaction mechanism will be developed for potential clinical use and will offer the prospects of higher efficacy and lower toxicity.